US4699915A - Substituted heterocyclyl-phenylformamidines and salts thereof - Google Patents
Substituted heterocyclyl-phenylformamidines and salts thereof Download PDFInfo
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- US4699915A US4699915A US06/751,087 US75108785A US4699915A US 4699915 A US4699915 A US 4699915A US 75108785 A US75108785 A US 75108785A US 4699915 A US4699915 A US 4699915A
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D233/91—Nitro radicals
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Definitions
- This invention relates to novel substituted heterocyclylphenylformamidines and acid addition salts thereof, to methods of preparing these compounds, to pharmaceutical compositions containing them as active ingredients, and to methods of using them as gastric acid secretion inhibitors and antiulcerogenics.
- H 1 -receptors It is known that classic antihistamines, such as mepyramine, are capable of antagonizing some effects of histamine mediated by H 1 -receptors. However, these compounds have no effect on gastric acid secretion which is instead affected by other antihistaminic agents defined by Black et al. (Nature 236, 385, 1972) as histamine H 2 -receptor antagonists. This has indicated that another kind of receptors (H 2 ) already described by Ash and Schild (Brit. J. Pharmacol. Chem. Ther. 1966, 27, 427-39), is involved in the gastric secretory response which is not blocked by the conventional antihistamines of the H 1 -type.
- H 2 -receptor antagonists capable of antagonizing gastric acid secretion include burimamide, metiamide, and cimetidine. More recently, new H 2 -antagonists, such as rantidine (Bradshaw et al., Brit. J. Pharmacol. 66, 464P, 1979), tiotidine (P. O. Jellin, Life Sci. 25, 2001, 1979) and BL 6341 (Cavanagh et al., Fed. Proc., 40, 2652, 1981) have been discovered. These compounds are effective H 2 -blockers capable of antagonizing gastric acid secretion to a greater extent than cimetidine and congeners. In copending U.S. application Ser. No.
- H 2 -antagonists namely imidazolyl-phenylamidines and guanidino-heterocyclylphenylamidines, which are potent H 2 -blockers and active antagonists of gastric acid secretion.
- H 2 -antagonists such as cimetidine, ranitidine, etc.
- phenylformamidine grouping bearing variously substituted imidazolyl- and guanidino-heterocyclyl rings.
- the present invention relates to a novel class of heterocyclyl-phenylformamidines represented by the formula ##STR2## wherein R is hydrogen or methyl;
- R 1 is straight or branched alkyl of 1 to 6 carbon atoms, hydroxy(alkyl of 1 to 6 carbon atoms), mono- or di-(alkoxy of 1 to 6 carbon atoms) (alkyl of 1 to 6 carbon atoms), (alkyl of 1 to 6 carbon atoms)thio(alkyl of 1 to 6 carbon atoms), cyano(alkyl of 1 to 6 carbon atoms), alkenyl, alkynyl or cycloalkyl;
- R 2 is hydrogen, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms or halogen
- X is pyrazol-3-yl, 1,2,4-triazol-3-yl, pyridin-2-yl, pyridin-3-yl, thiazol-4-yl, 2-methyl-thiazol-4-yl or 2-methylamino-thiazol-4-yl;
- R 1 when R 1 is hydroxy(alkyl of 1 to 6 carbon atoms) it may be hydroxypropyl or hydroxybutyl; when R 1 is mono- or di-(alkoxy of 1 to 6 carbon atoms) it may be hydroxypropyl or hydroxybutyl; when R 1 is mono- or di-(alkoxy of 1 to 6 carbon atoms) (alkyl of 1 to 6 carbon atoms) it may be mono- or dimethoxyethyl or methoxypropyl; when R 1 is (alkyl of 1 to 6 carbon atoms)thio(alkyl of 1 to 6 carbon atoms) it may be methylthioethyl or ethylthioethyl; when R 1 is cyano(alkyl of 1 to 6 carbon atoms) it may be cyanoethyl; when R 1 is alkenyl it may be alkenyl of 3 to 5 carbon atoms; when R 1 is alkynyl it may be al
- the formamidine radical may be in the ortho-, meta- or para-position of the benzene ring with respect to X, and substituent R 2 may be in any position on the benzene ring.
- Such compounds generally have better activity and are therefore preferred as antisecretory-antiulcer agents and for the treatment of disorders of the gastrointestinal tract.
- the compounds of the formula I may, for example, be prepared by the following method:
- R 1 has the meanings previously defined.
- the reaction may conveniently be performed in the presence of water or of an inert aqueous organic solvent, for example in a lower alkanol such as methanol or ethanol, formamide, dimethylformamide, dioxane or acetonitrile.
- a lower alkanol such as methanol or ethanol, formamide, dimethylformamide, dioxane or acetonitrile.
- the reaction is generally carried out at a temperature from 10° to 50° C., preferably at room temperature.
- the compounds of the formula II used as starting material in this method may be prepared by methods which are described in the literature, for example, by reacting an amine of the formula ##STR4## wherein X, R and R 2 have the meanings previously defined, with an N-cyano-alkylimidate of the formula ##STR5## in which Y is lower alkyl, such as methyl or ethyl.
- the reaction may generally be carried out in the presence of a suitable inert organic solvent, such as a lower alkanol, an ether, ethylacetate, acetonitrile or dioxane, or also without solvent, at a temperature from 20° to 80° C., preferably at room temperature.
- the compounds of the formula II may be prepared in a single step by reacting an amine of the formula IV with cyanamide in the presence of a compound of the formula ##STR6## in which Y has the meaning previously defined. The reaction is carried out at a temperature of 50° to 150° C.
- the compounds of the formula I prepared according to the above method may optionally be converted with inorganic or organic acids into non-toxic, pharmacologically acceptable acid addition salts, for example by conventional methods such as by reacting the compounds as bases with a solution of the corresponding acid in a suitable solvent, or by adding the acid solution directly to the reaction mixture obtained in the method without isolation of the compound as a base.
- Particularly preferred acids include for example hydrochloric, sulfuric, maleic and fumaric acid.
- the compounds of the formula I and their non-toxic, pharmacologically acceptable acid addition salts are H 2 -receptor blocking agents which inhibit gastric acid secretion.
- Particularly preferred compounds of the present invention are the following:
- Nitrate (ethanol); M.p. 141° C. (dec.).
- Tartrate ethyl acetate
- Tartrate ethyl acetate
- the compounds embraced by formula I above and their nontoxic, pharmacologically acceptable acid addition salts have useful pharmacodynamic properties. More particularly, they exhibit antiulcerogenic and gastric acid secretion inhibiting activities in warm-blooded animals such as rats.
- the antagonistic activity of the compounds of the invention on histamine H 2 -receptors is demonstrated either in vitro or in vivo by their inhibition of the H 2 -dependent biological effects, which include the histamine-evoked positive chronotropic effect and the histamine-induced gastric secretion of acid respectively.
- the inhibition of the positive chronotropic effect was investigated on isolated guinea pig atria suspended in an organ bath (50 ml) containing an oxygenated (O 2 :95%-CO 2 :5%) Krebs-Henseleit solution (pH 7.4) maintained at 32° C.
- the myocardial preparation loaded with 1 g isometric tension, was allowed to stabilize 60 minutes, and myocardial contractions were recorded through an isometric lever connected to a strain-gauge coupler and the instantaneous rate was monitored with a cardiotachometer, and a heatwriting pen recorder.
- the test compound was added to the bath at the desired final concentration and left for 30 minutes before the atria were again challenged with histamine.
- the chronotropic response obtained in the presence of the antagonist was then compared to the control response to histamine, and the percent reduction of the histamine H 2 -evoked response was calculated.
- the average effective concentration (EC 50 ) of the H 2 -antagonists was also calculated by standard procedure according to Dr. Waud, Analysis of Dose-Response Curves, in "Methods in Pharmacology" vol. 3, Smooth muscle, Ed. Daniel E. E. Paton, M., Plenum Press, New York (1975); Ash and Schild, Br. J. Pharmacol. Chemother. 27, 427-439, 1966. The following table shows the results which were obtained.
- test compounds to inhibit histamine-induced gastric secretion of acid was investigated after intravenous or intraduodenal administration in stomach-perfused rats, according to Gosh and Schild (Br. J. Pharmacol. Chemother. 13, 54, 1958).
- PE 50 polyethylene tubes
- the compounds of the present invention are administered to warm-blooded animals perorally or parenterally as active ingredients in customary pharmaceutical compositions, that is, compositions consisting essentially of an inert pharmaceutical carrier and an effective amount of the active ingredient, such as tablets, coated pills, capsules, wafers, solutions, suspensions, emulsions, syrups, suppositories and the like.
- An effective amount of the compounds according to the present invention is from 0.14 to 7.14 mgm/kg body weight, preferably 0.28 to 2.14 mgm/kg body weight.
- compositions comprising a compound of the present invention as an active ingredient and represent the best modes contemplated of using the invention.
- the parts are parts by weight unless otherwise specified.
- the tablet composition is compounded from the following ingredients:
- the active ingredient, the lactose and the corn starch are mixed and homogeneously moistened with water. After screening of the moist mass and drying in a tray driver, the mixture is again passed through a screen and magnesium stearate is added. Then, the mixture is compressed into tablets weighing 300 mg each. Each tablet contains 50 mg of the active ingredient.
- the capsule filler composition is compounded from the following ingredients:
- the active ingredient is mixed with the excipients, and the mixture is passed through a screen and homogeneously mixed in a suitable device.
- the resulting mixture is filled into hard gelatin capsules (222 mg per capsule); each capsule contains 50 mg of the active ingredient.
- the solution is compounded from the following ingredients:
- the active ingredient is dissolved in the water, and the resulting solution is filled into 5 cc-ampules under sterile conditions. Each ampule contains 50 mg of the active ingredient.
- any one of the other compounds embraced by formula I or a non-toxic, pharmacologically acceptable acid addition salt thereof may be substituted for the particular active ingredient in Examples 11 through 13.
- the amount of active ingredient in these illustrative examples may be varied to achieve the dosage unit range set forth above, and the amounts and nature of the inert pharmaceutical carrier ingredients may be varied to meet particular requirements.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Furan Compounds (AREA)
- Pyridine Compounds (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT21331/82A IT1201523B (it) | 1982-05-18 | 1982-05-18 | Eterociclilfenilfomramidine,processi per la loro preparazione e loro uso farmaceutico |
IT21331A/82 | 1982-05-18 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US06491367 Continuation-In-Part | 1983-05-04 |
Publications (1)
Publication Number | Publication Date |
---|---|
US4699915A true US4699915A (en) | 1987-10-13 |
Family
ID=11180218
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US06/751,087 Expired - Fee Related US4699915A (en) | 1982-05-18 | 1985-07-02 | Substituted heterocyclyl-phenylformamidines and salts thereof |
US06/751,081 Expired - Fee Related US4666932A (en) | 1982-05-18 | 1985-07-02 | Formamidine derivatives and pharmaceutical use |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US06/751,081 Expired - Fee Related US4666932A (en) | 1982-05-18 | 1985-07-02 | Formamidine derivatives and pharmaceutical use |
Country Status (4)
Country | Link |
---|---|
US (2) | US4699915A (fr) |
EP (1) | EP0094727A3 (fr) |
JP (1) | JPS58213757A (fr) |
IT (1) | IT1201523B (fr) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5190961A (en) * | 1990-08-03 | 1993-03-02 | Terumo Kabushiki Kaisha | Thiourea derivatives and antimicrobial agent and antulcer agent containing the same |
US5243055A (en) * | 1990-12-19 | 1993-09-07 | Givaudan Corporation | Heterocyclic formamidines useful as ultraviolet light absorbers |
WO2012029032A2 (fr) | 2010-09-03 | 2012-03-08 | Piramal Life Sciences Limited | Composés hétérocycliques en tant qu'inhibiteurs de dgat1 |
WO2022034121A1 (fr) | 2020-08-11 | 2022-02-17 | Université De Strasbourg | Bloqueurs de h2 ciblant des macrophages du foie pour la prévention et le traitement d'une maladie du foie et du cancer |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2106337C (fr) * | 1992-09-26 | 1998-06-16 | Hiroyuki Nakanishi | Derives phenylimidazole, procedes pour leur production, herbicides les comprenant, et leurs usages a titre d'herbicides |
AUPP873799A0 (en) * | 1999-02-17 | 1999-03-11 | Fujisawa Pharmaceutical Co., Ltd. | Pyridine compounds |
FR2842808B1 (fr) * | 2002-07-25 | 2004-09-10 | Sod Conseils Rech Applic | Nouveaux derives d'arylimidazoles, leur preparation et leurs applications therapeutiques |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1296544A (fr) * | 1969-10-29 | 1972-11-15 | ||
US4386099A (en) * | 1980-11-28 | 1983-05-31 | Istituto De Angeli S.P.A. | Imidazolylphenyl amidines, pharmaceutical compositions containing same and use thereof |
US4438127A (en) * | 1976-03-11 | 1984-03-20 | Smith Kline & French Laboratories Limited | Pharmacologically active compounds |
-
1982
- 1982-05-18 IT IT21331/82A patent/IT1201523B/it active
-
1983
- 1983-05-16 EP EP83200690A patent/EP0094727A3/fr not_active Withdrawn
- 1983-05-18 JP JP58087371A patent/JPS58213757A/ja active Pending
-
1985
- 1985-07-02 US US06/751,087 patent/US4699915A/en not_active Expired - Fee Related
- 1985-07-02 US US06/751,081 patent/US4666932A/en not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1296544A (fr) * | 1969-10-29 | 1972-11-15 | ||
US4438127A (en) * | 1976-03-11 | 1984-03-20 | Smith Kline & French Laboratories Limited | Pharmacologically active compounds |
US4386099A (en) * | 1980-11-28 | 1983-05-31 | Istituto De Angeli S.P.A. | Imidazolylphenyl amidines, pharmaceutical compositions containing same and use thereof |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5190961A (en) * | 1990-08-03 | 1993-03-02 | Terumo Kabushiki Kaisha | Thiourea derivatives and antimicrobial agent and antulcer agent containing the same |
US5243055A (en) * | 1990-12-19 | 1993-09-07 | Givaudan Corporation | Heterocyclic formamidines useful as ultraviolet light absorbers |
US5436338A (en) * | 1990-12-19 | 1995-07-25 | Givaudan-Roure Corporation | Heterocyclic formamidines useful as ultraviolet light absorbers |
WO2012029032A2 (fr) | 2010-09-03 | 2012-03-08 | Piramal Life Sciences Limited | Composés hétérocycliques en tant qu'inhibiteurs de dgat1 |
WO2022034121A1 (fr) | 2020-08-11 | 2022-02-17 | Université De Strasbourg | Bloqueurs de h2 ciblant des macrophages du foie pour la prévention et le traitement d'une maladie du foie et du cancer |
Also Published As
Publication number | Publication date |
---|---|
IT1201523B (it) | 1989-02-02 |
IT8221331A0 (it) | 1982-05-18 |
EP0094727A3 (fr) | 1985-01-09 |
US4666932A (en) | 1987-05-19 |
JPS58213757A (ja) | 1983-12-12 |
EP0094727A2 (fr) | 1983-11-23 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: ISTITUTO DE ANGELI S.P.A., VIA SERIO 15, 20139 MIL Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:CEREDA, ENZO;BIETTI, GIUSEPPE;DONETTI, ARTURO;AND OTHERS;REEL/FRAME:004615/0879 Effective date: 19860617 |
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CC | Certificate of correction | ||
REMI | Maintenance fee reminder mailed | ||
LAPS | Lapse for failure to pay maintenance fees | ||
FP | Lapsed due to failure to pay maintenance fee |
Effective date: 19911013 |
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STCH | Information on status: patent discontinuation |
Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362 |